Nuclear Matrix Factor hnRNP U/SAF-A Exerts a Global Control of Alternative Splicing by Regulating U2 snRNP Maturation

SummaryThe nuclear matrix-associated hnRNP U/SAF-A protein has been implicated in diverse pathways from transcriptional regulation to telomere length control to X inactivation, but the precise mechanism underlying each of these processes has remained elusive. Here, we report hnRNP U as a regulator of SMN2 splicing from a custom RNAi screen. Genome-wide analysis by CLIP-seq reveals that hnRNP U binds virtually to all classes of regulatory noncoding RNAs, including all snRNAs required for splicing of both major and minor classes of introns, leading to the discovery that hnRNP U regulates U2 snRNP maturation and Cajal body morphology in the nucleus. Global analysis of hnRNP U-dependent splicing by RNA-seq coupled with bioinformatic analysis of associated splicing signals suggests a general rule for splice site selection through modulating the core splicing machinery. These findings exemplify hnRNP U/SAF-A as a potent regulator of nuclear ribonucleoprotein particles in diverse gene expression pathways.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (144 K)Download as PowerPoint slideHighlights► Identify hnRNP U/SAF-A in regulating SMN2 splicing from a RNAi screen ► Reveal genomic interaction of hnRNP U with RNA, including all snRNAs for splicing ► Show enhanced U2 snRNP maturation in response to hnRNP U depletion ► Globally correlate enhanced U2 snRNP maturation to hnRNP U-regulated splicing